Clinical Trials Register

Summary
EudraCT Number:	2014-002601-38
Sponsor's Protocol Code Number:	D5010C00009
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-02-17
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2014-002601-38

A.3

Full title of the trial

A 24-Month, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Efficacy, Safety, Tolerability, Biomarker and Pharmacokinetics Study of AZD3293 in Early Alzheimer’s Disease (The AMARANTH Study)

Az AZD3293 hatásosságának, biztonságosságának, tolerálhatóságának biomarkeres és farmakokinetikai, 24 hónapos, többközpontú, randomizált, kettősvak, placebo kontrollált, párhuzamos csoportos vizsgálata korai Alzheimer-kór esetén (Amaranth vizsgálat)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study to assess the effect of AZD3293 in early Alzheimer's Disease

Az AZD3293 hatásosságának vizsgálata korai Alzheimer-kór esetén

A.3.2

Name or abbreviated title of the trial where available

The AMARANTH Study

A.4.1

Sponsor's protocol code number

D5010C00009

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Eli Lilly and Company
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Eli Lilly and Company
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Eli Lilly
B.5.2	Functional name of contact point	Clinical Trial Registry Office
B.5.3	Address:
B.5.3.1	Street Address	Lilly Corporate Center, DC 1526
B.5.3.2	Town/ city	Indianapolis
B.5.3.3	Post code	46285
B.5.3.4	Country	United States
B.5.6	E-mail	EU_Lilly_Clinical_Trials@lilly.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	AZD3293 20mg
D.3.2	Product code	AZD3293
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not yet available
D.3.9.1	CAS number	1522418-41-2
D.3.9.2	Current sponsor code	AZD3293
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	AZD3293 50mg
D.3.2	Product code	AZD3293
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not yet available
D.3.9.1	CAS number	1522418-41-2
D.3.9.2	Current sponsor code	AZD3293
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Early Alzheimer’s Disease (mild cognitive impairment due to AD (ie, prodromal AD) and mild dementia of the Alzheimer’s type)

E.1.1.1

Medical condition in easily understood language

Early Alzheimer’s Disease

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10012271
E.1.2	Term	Dementia Alzheimer's type
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To test the hypothesis that AZD3293, administered orally at doses of 20 and 50 mg daily for 104 weeks, will slow the decline of AD as compared with placebo in patients with early AD dementia as measured by ADAS-Cog13

E.2.2

Secondary objectives of the trial

•To evaluate the efficacy of AZD3293 on functional, clinical, and cognitive outcomes at the end of the Double-Blind Treatment period (Week 104)
•To evaluate the relationship between treatment effect of AZD3293 and time
•To test the hypothesis that AZD3293 will slow the rate of cognitive and functional decline associated with AD, compared with placebo
•To evaluate the efficacy of AZD3293 to prolong time in the current disease state
•To evaluate the clinical worsening and need for symptomatic treatments
•To evaluate the effect of AZD3293 on brain atrophy as measured by brain volumes using MRI
•To assess the population pharmacokinetics of AZD3293 and metabolite AZ13569724
•To evaluate the safety and tolerability of AZD3293

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

•To evaluate the effect of AZD3293 on brain amyloid burden using positron emission tomography (PET) in the longitudinal PET sub-study (included in the main protocol).

•To evaluate the effect of AZD3293 on brain metabolic rates using fluorodeoxyglucose (FDG) PET

CSF longitudinal sub-study (included in main protocol):
To evaluate the effect of AZD3293 on CSF amyloid beta peptide pharmacodynamics markers and markers of neurodegeneration (total tau and phosphorylated tau)

E.3

Principal inclusion criteria

•Gradual and progressive change in the patient’s memory function over more than 6 months
•Male or female, aged 55 to 85 years inclusive
•MMSE score of 20 to 30 inclusive
•Score of ≤ 85 on the Delayed Memory Index of the Repeatable Battery for the assessment of Neuropsychological Status (RBANS)
•For a diagnosis of mild AD, patient (1) meets the National Institute on Aging (NIA) and the Alzheimer’s Association (AA) (NIA-AA) criteria for probable AD and (2) has a CDR global score of 0.5 or 1, with the memory box score ≥0.5
•For a diagnosis of MCI due to AD, patient (1) meets NIA-AA criteria for MCI due to AD and (2) has a CDR global score of 0.5, with the memory box score ≥0.5
•Laboratory tests show no evidence of other etiologies for MCI or dementia
•PET visual reading or CSF Ab1-42 concentration positive for presence of amyloid
•Contraception: Women must be postmenopausal, surgically sterile or infertile due to congenital abnormality. Men must abstain or use barrier contraception from the first day of dosing until 3 months after the last dose and abstain for 24 hours after amyloid PET scans
•All medication dosing should be stable for at least 30 days before screening, and between screening and randomization (does not apply to medications discontinued during screening, medications taken as needed, and / or medications not expected to substantially influence safety or efficacy assessments, in the opinion of the investigator, at baseline).
•Treatment with memantine must be discontinued at least 3 weeks before randomization
•Agreement to undergo ApoE genotyping
•The patient must have a reliable study partner with whom he/she cohabits or has regular contact

E.4

Principal exclusion criteria

•Prior or ongoing participation in another clinical trial or medical research judged not to be scientifically or medically compatible
•Significant and/or current neurological disease affecting the CNS, other than AD, that may affect cognition or ability to complete the study
•History of clinically evident stroke or multiple strokes based on history or imaging results
•History of clinically important carotid or vertebrobasilar stenosis or plaque
•History of multiple concussions or a concussion with sustained cognitive complaints or objective change in neuropsychological function in the last 5 years
•Patients with a current DSM-V diagnosis of Major Depressive Disorder or any current primary psychiatric diagnosis other than AD if, the psychiatric disorder or symptom is likely to confound interpretation of drug effect, affect cognitive assessment, or affect the patient’s ability to complete the study, history of schizophrenia or other chronic psychosis
•History of alcohol, drug abuse or dependence (except nicotine dependence) within the last 2 years
•Within 1 year before the screening visit or between screening and baseline: myocardial infarction; moderate or severe congestive heart failure, NYHA class III or IV; hospitalization for, or symptoms of, unstable angina; syncope due to orthostatic hypotension or unexplained syncope; known significant structural heart disease; hospitalization for arrhythmia
•Congenital QT prolongation
•Intermittent second- or third-degree AV heart block or AV dissociation or history of ventricular tachycardia
•History of cancer within the last 5 years, with the exception of non-metastatic basal and/or squamous cell carcinoma of the skin, in situ cervical, or non-progressive prostate cancer or cancers with low risk of recurrence or spread
•Current serious or unstable clinically important systemic illness likely to affect cognitive assessment, deteriorate, or affect the patient’s safety or ability to complete the study , including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic, or hematologic disorders
•History of vitiligo and/or current evidence of post-inflammatory hypopigmentation or exposure to depigmenting agents in the 6 months prior to screening
•History of 2 or more clinically important drug allergies, eg, severe drug-induced rash or anaphylaxis
•Screening MRI shows evidence of significant abnormality that would suggest
another potential etiology for MCI or dementia
•Uncontrolled hypertension
•A corrected QT (QTcF) interval measurement >470 msec
•Positive serologic findings for HIV antibodies
•Positive hepatitis B surface antigen or hepatitis C virus antibodies
•Urine drug screen positive for inappropriate drug use
•Any clinically important abnormality at screening
•Calculated creatinine clearance <30 mL/min
•ALT ≥2 × the upper limit of normal (ULN) of the performing laboratory, AST
≥2 × ULN, total bilirubin ≥1.5 × ULN or ALP ≥1.5 x ULN
•Use of medications that would interfer with cognitive testing
•Use of strong inhibitors of CYP3A4 within 14 days or 5 half-lives, whichever is
longer, or strong inducers of CYP3A4 within 30 days before randomisation
•Use of strong inhibitors of Pgp or BCRP within 14 days or 5 half-lives, whichever is longer, before randomisation or inducers of Pgp within 30 days before baseline
•For patients undergoing lumbar puncture, use of medications known to significantly influence coagulation, such as warfarin or heparin
•Treatment with any investigational drug or device within 60 days or 5 half-lives prior to screening (whichever is longer) or between screening and randomisation
•Prior treatment with an AD vaccine
•Presence of any of the following MRI contraindications: pacemaker; cardiac
defibrillator; spinal cord or vagus nerve stimulator; aneurysm clip; artificial heart valve; coronary or carotid stent; ear implant; CSF shunt; other implanted medical device; metal fragments or foreign objects in the eyes, skin or body; severe claustrophobia
CSF sub-study:
•Any spinal malformations or other aspects/clinical findings that may complicate or contraindicate lumbar puncture
•Current blood-clotting or bleeding disorder, including clinically significant abnormal findings in laboratory assessments of coagulation or hematology
PET sub-study:
•Present or planned participation in any other research and/or medical protocol involving PET ligands or radioactive agents
•Exposure to ionizing radiation that, in combination with the planned administration of study amyloid PET ligand, would result in a cumulative exposure exceeding local recommended limits
•Hypersensitivity to the active substance or excipients of AMYVID

E.5 End points

E.5.1

Primary end point(s)

Alzheimer’s Disease Assessment Scale – Cognitive subscale (ADASCog13)

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline up to 104 Weeks

E.5.2

Secondary end point(s)

Efficacy
•Change from baseline to Week 104 in the FAQ score, ADCS-iADL instrumental items score, Integrated Alzheimer’s Disease Rating Scale (iADRS) score, Sum of Boxes (CDR-SB) score, CDR-Global Score, NPI total score and Mini-Mental State Examination (MMSE)
•Changes from baseline in the CDR-SB, ADAS-Cog-13, FAQ, ADCS-iADL instrumental items, and iADRS score across time
•AD symptomatic treatments time of initiation

Biomarker
•Changes from screening in volumetric MRI measures
CSF sub-study:
•Changes from screening in CSF Aβ1-40 and Aβ1-42
•Changes from screening in CSF biomarkers total tau and phosphorylated tau
PET sub-study:
•Change from screening in brain amyloid as measured by amyloid PET
•Change from baseline in brain metabolism as measured by FDG PET

Safety:
•Frequencies of clinically significant changes in physical examination findings, including results of neurological, skin, and eye examinations
•Frequencies of spontaneously reported adverse events (AEs)
•Changes in vital signs and body weight
•Changes in ECG and serial MRI findings
•Changes in clinical laboratory test results
•Changes in Columbia - Suicide Severity Rating Scale (C-SSRS) scores

Pharmacokinetic
•Apparent Oral Clearance of AZD3293
•Central Volume of Distribution of AZD3293

E.5.2.1

Timepoint(s) of evaluation of this end point

All safety endpoints will be evaluated at all time points from screening.
Time points for the primary and secondary efficacy endpoints that will be tested through a step-down approach.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Canada

Japan

Korea, Republic of

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

136

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

768

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

Information not present in EudraCT

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

904

F.4.2.2

In the whole clinical trial

2202

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

It is anticipated the first subject ending treatment will be in 2017.
Completers will be offered participation in a separate long term
extension trial if they so wish and the CTA application for this trial is approved.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-02-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-02-10

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-10-04

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